IMPORTANCEThe genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood.OBJECTIVE To explore the genetic basis of BD in the Han Chinese population. DESIGN, SETTING, AND PARTICIPANTSA genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020.MAIN OUTCOMES AND MEASURES Single-nucleotide variations with P < 5.00 × 10 −8 were considered to show genome-wide significance of statistical association. RESULTS The HanChinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189[58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10 −8 ; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρ ge = 0.652, SE = 0.106; P = 7.30 × 10 −10 ) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R 2 = 1.27%; P = 1.30 × 10 −19 ) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10 −9 ; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10 −8 ; OR, 0.932; 95% CI, 0.909-0.956).CONCLUSIONS AND RELEVANCE This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Technical developments and improved access to neuroimaging techniques has brought us closer to understanding the neuropathological origins of schizophrenia. Using data-driven disease progression modelling on cross-sectional MRIs from 1124 schizophrenia patients, we characterize two distinct but stable 'trajectories' of brain atrophy, separately beginning in the Broca's area (subtype1) and the hippocampus (subtype2). The two 'trajectories' are replicated in cross-validation samples. Individuals within each subtype are further classified into two stages ('pre-atrophy' and 'post-atrophy'). These subtypes show different atrophy patterns and symptom profiles. Longitudinal data from 523 schizophrenia patients treated by antipsychotics only (APM) or adjunct transcranial magnetic stimulation (TMS) reveal that APM effects relate to phenotypic subtype (more effective in the subtype1) while TMS effects relate to the stage (superior outcomes in the 'pre-atrophy' stage). These findings suggest distinct pathophysiological processes underlying schizophrenia that potentially yield to stratification and prognostication -a key requirement for personalizing treatments in enduring illnesses. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2000041106).

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, the genetic and phenotypic heterogeneity of the illness has hampered the discovery of its genetic determinants. In this study, in an independent Han Chinese sample (1824 MDD cases and 3031 controls), we conducted replication analyses of two genetic loci highlighted in a previous Chinese MDD genome-wide association study (GWAS), and confirmed the significant association of a single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Besides, in independent Han Chinese postmortem brain and peripheral blood samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies.

Urbanization is increasing globally, and is associated with stress and increased mental health risks, including for depression. However, it remains unclear, especially at the level of brain function, how urbanicity, social threat stressors, and psychiatric risk may be linked. Here, we aim to define the structural and functional MRI neural correlates of social stress, childhood urbanicity, and their putative mechanistic relevance to depressive illness risk, in terms of behavioral traits and genetics. We studied a sample of healthy adults with divergent urban and rural childhoods. We examined childhood urbanicity effects on brain structure as suggested by MRI, and its functional relevance to depression risk, through interactions between urbanicity and trait anxiety-depression, as well as between urbanicity and polygenic risk for depression, during stress-related medial prefrontal cortex (mPFC) engagement. Subjects with divergent rural and urban childhoods were similar in adult socioeconomic status and were genetically homogeneous. Urban childhood was associated with relatively reduced mPFC gray matter volumes as suggested by MRI. MPFC engagement under social status threat correlated with the higher trait anxiety-depression in subjects with urban childhoods, but not in their rural counterparts, implicating an exaggerated physiological response to the threat context with urbanicity, in association with behavioral risk for depression. Stress-associated mPFC engagement also interacted with polygenic risk for depression, significantly predicting a differential mPFC response in individuals with urban but not rural childhoods. Developmental urbanicity, therefore, appears to interact with genetic and behavioral risk for depression on the mPFC neural response to a threat context.

Backgrounds: Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) are classified as two chronic psychiatric disorders with high comorbidity rate and shared clinical symptoms. Abnormal spontaneous brain activity within the cortical–striatal neural circuits has been observed in both disorders. However, it is unclear if the common or distinct neural abnormalities underlie the neurobiological substrates in the resting state.Methods: Resting-state fMRI data were collected from 88 patients with SCZ, 58 patients with OCD, and 72 healthy control subjects. First, we examined differences in amplitude of low-frequency fluctuations (ALFF) among three groups. Resting-state functional connectivity (rsFC) analysis with the brain region that showed different ALFF as the seed was then conducted to identify the changes in brain networks. Finally, we examined the correlation between the altered activities and clinical symptoms.Results: Both the patients with SCZ and OCD showed increased ALFF in the right hippocampus and decreased ALFF in the left posterior cingulate cortex (PCC). SCZ patients exhibited increased ALFF in the left caudate [voxel-level family-wise error (FWE) P &lt; 0.05] and decreased rsFC between the left caudate and right cerebellum, which correlated with positive symptoms. The left caudate showed increased rsFC with the right thalamus and bilateral supplementary motor complex (SMC) in OCD patients (cluster-level FWE P &lt; 0.05).Conclusions: The hippocampus and PCC are common regions presenting abnormal local spontaneous neuronal activities in both SCZ and OCD, while the abnormality of the striatum can reflect the differences. Increased ALFF in the striatum and symptom-related weakened rsFC between the caudate and cerebellum showed SCZ specificity. Enhanced rsFC between the caudate and SMC may be a key characteristic in OCD. Our research shows the similarities and differences between the two diseases from the perspective of resting-state fMRI, which provides clues to understand the disease and find methods for treatment.